Rescuing ⍺-synuclein toxicity through neuron-specific enhancement of autophagy

通过神经元特异性增强自噬来解除α-突触核蛋白毒性

基本信息

批准号：
10664568
负责人：
Jason Paul Chua
金额：
$ 20.2万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664568
关键词：
Acceleration Address Adverse effects Affect Automobile Driving Autophagocytosis Autophagosome Bioinformatics Biological Models Biology CRISPR interference CRISPR screen Cell Death Cell model Cells Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Cytoplasmic Inclusion Cytoprotection Development Plans Disease Disease Progression Disease model Doctor of Medicine Doctor of Philosophy Educational workshop Fellowship Genes Goals Half-Life Home Human Imaging Techniques Impairment Induced pluripotent stem cell derived neurons Institution Investigation Knowledge Label Late-Onset Disorder Learning Measures Mentors Mentorship Metabolism Methods Motor Movement Disorders Nerve Degeneration Neurodegenerative Disorders Neurology Neurons Neurosciences Research North America Optics Parkinson Disease Pathogenesis Pathology Pathway interactions Patients Persons Phosphatidylinositols Phosphoric Monoester Hydrolases Physicians Physiologic pulse Population Positioning Attribute Predisposing Factor Principal Investigator Program Development Proteins Publishing Recycling Regulation Research Research Technics Residencies Resources Scientist Spinobulbar Muscular Atrophy Stimulus Symptoms Testing Therapeutic Tissues Toxic effect Training Transcript Work alpha synuclein career career development cell type design disability experience genome-wide high throughput screening induced pluripotent stem cell innovation knock-down mTOR inhibition meetings mouse model mutant myotubularin neuron loss neuronal survival neuroprotection novel nutrient deprivation prevent proteostasis proteotoxicity skills symptom management therapeutic target therapy design therapy development translational neuroscience

项目摘要

Project Summary This proposal outlines a five-year career development program aimed at promoting the principal investigator to research independence as a clinician scientist in basic and translational neuroscience, with specialization in cell type-specific mechanisms that regulate neuronal autophagy and modify proteotoxicity in Parkinson disease (PD). Applicant: The applicant has completed M.D. and Ph.D. degrees, residency training in neurology, and fellowship training in PD and movement disorders. He has previous experience in neuroscience research using cell and mouse models to study autophagy in spinobulbar muscular atrophy. His career development plan is designed to focus his research on PD pathogenesis and advance his knowledge in bioinformatics, CRISPR gene editing and high-throughput screening, and advanced imaging techniques. In so doing, the training plan outlined herein builds upon his prior training to achieve research independence. He will benefit from continual mentor engagement, regular meetings and ongoing collaborations. He will learn additional research techniques through formal coursework, workshops, and national meetings. These training mechanisms will provide the applicant with the scientific and conceptual skillset necessary for an independent career in neurodegenerative research. Research Plan: PD is a progressive neurodegenerative disorder marked by motor and non-motor/multi-systemic symptoms that lead to profound disability. There is no effective disease-modifying therapy currently available. Neurodegeneration in PD relates to toxic aggregation of ⍺-synuclein, and mounting evidence shows that ⍺- synuclein can be degraded through the conserved pathway of autophagy. However, current methods to modulate autophagy fail to confer neuroprotective effects in patients. In recently published work, the applicant identified MTMR5 (myotubularin-related phosphatase 5, encoded by the SBF1 transcript) as a potent neuronal autophagy suppressor in neurons. MTMR5 knockdown enhances the sensitivity of neurons to induction of autophagy, and accelerates the degradation of multiple autophagy substrates, including disease-associated and aggregate- prone proteins. In line with this, this proposal will test the central hypothesis that reducing MTMR5 in neurons augments autophagic clearance of ⍺-synuclein and reduces ⍺-synuclein-related neuronal death. The applicant will use human induced pluripotent stem cells (iPSCs) to determine if manipulating SBF1/MTMR5 enhances ⍺- synuclein turnover via autophagy (Aim 1) and modifies ⍺-synuclein proteotoxicity (Aim 2). He will also employ unbiased, genome-wide CRISPR-based screens to uncover key factors regulating MTMR5 in neurons (Aim 3). Collectively, these studies establish a novel research platform focusing on neuronal autophagy, myotubularin biology, and therapy design in PD and related neurodegenerative disorders.

项目概要该提案概述了一个五年职业发展计划，旨在促进首席研究员作为基础和转化神经科学领域的临床科学家，具有独立的研究能力，专长于细胞调节神经元自噬和改变帕金森病（PD）蛋白毒性的类型特异性机制。申请人：申请人已完成医学博士和博士学位、神经病学住院医师培训和研究员资格。他拥有使用细胞和运动进行神经科学研究的经验。他的职业发展计划旨在研究脊髓延髓肌萎缩症的自噬作用。他的研究重点是 PD 发病机制，并提高了他在生物信息学、CRISPR 基因编辑和高通量筛选和先进的成像技术在此概述了培训计划。他将在之前的培训基础上获得研究独立性，他将受益于持续的导师。他将通过参与、定期会议和持续合作学习更多的研究技术。这些培训机制将为申请人提供正式的课程作业、研讨会和国家会议。具有神经退行性研究独立职业所需的科学和概念技能。研究计划：PD是一种进行性神经退行性疾病，以运动和非运动/多系统疾病为特征目前尚无有效的疾病缓解疗法。 PD 中的神经变性与 ⍺-突触核蛋白的毒性聚集有关，越来越多的证据表明 ⍺- 突触核蛋白可以通过自噬的保守途径降解，但是目前的调节方法。申请人在最近发表的研究中指出，自噬无法对患者产生神经保护作用。 MTMR5（肌管蛋白相关磷酸酶 5，由 SBF1 转录本编码）作为有效的神经元自噬神经元中的抑制因子。MTMR5 敲低增强了神经元对自噬诱导的敏感性，并且加速多种自噬底物的降解，包括疾病相关底物和聚合底物与此相符，该提案将测试减少神经元中 MTMR5 的中心假设。增强⍺-突触核蛋白的自噬清除并减少⍺-突触核蛋白相关的神经元死亡。将使用人类诱导多能干细胞 (iPSC) 来确定操纵 SBF1/MTMR5 是否会增强 ⍺- 通过自噬进行突触核蛋白周转（目标 1）并修改 ⍺-突触核蛋白蛋白毒性（目标 2）。基于 CRISPR 的公正的全基因组筛选，以揭示神经元中调节 MTMR5 的关键因素（目标 3）。总的来说，这些研究建立了一个专注于神经元自噬、肌管蛋白的新型研究平台 PD 和相关神经退行性疾病的生物学和治疗设计。